The goal of this Drug Discovery Group has been to develop anti-HIV-1 treatment strategies based on antisense methodology, and, during the initial two years of this project, we have developed the feasibility of antiviral RNA, in particular ribozyme, as a potentially selective agent for this virus inhibition. In the continuation of this project, we will focus on the development of antiviral RNA through a collaborative effort involving biologic, biophysical, chemical, and virologic disciplines. There are four component programs involved in this effort: 1. The Beckman Research Institute of the City of Hope, Duarte CA (J. Rossi, project leader). This project will study the bioactivity and stability of modified ribozymes and of other antisense RNA expression systems. 2. United States Biochemical Corporation, Cleveland, OH (J. Chase, project leader). This project will develop rapid enzymatic screening assays for characterization for new ribozymes and will devise improved industrial methods for chemical and enzymatic synthesis of ribozyme. 3. Children's Hospital of Los Angeles CA (D. Kohn, project leader). This project will use retroviral transduction of ribozyme in hematopoietic cells and will evaluate the stability of this expression and the occurence of toxicity in normal cells and in a mouse model of bone marrow transplantion. 4. City of Hope Medical Center, Duarte CA (J. Zaia, project leader). This project will evaluate the antiviral efficacy, specificity, toxicity, and natural resistance of HIV-1 specific ribozymes by comparing synthetic ribozymes, retroviral-transduced ribozymes in HIV-1 susceptible cells.